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{"title":"Conditional loss of Ube3d in the retinal pigment epithelium accelerates age-associated alterations in the retina of mice","authors":"Tianchang Tao, Ningda Xu, Jiarui Li, Mingwei Zhao, Xiaoxin Li, Lvzhen Huang","doi":"10.1002/path.6201","DOIUrl":null,"url":null,"abstract":"<p>Several studies have suggested a correlation between the ubiquitin-proteasome system (UPS) and age-related macular degeneration (AMD), with its phenotypic severity ranging from mild visual impairment to blindness, but the mechanism for UPS dysfunction contributing to disease progression is unclear. In this study, we investigated the role of ubiquitin protein ligase E3D (UBE3D) in aging and degeneration in mouse retina. Conditional knockout of <i>Ube3d</i> in the retinal pigment epithelium (RPE) of mice led to progressive and irregular fundus lesions, attenuation of the retinal vascular system, and age-associated deterioration of rod and cone responses. Simultaneously, RPE-specific <i>Ube3d</i> knockout mice also presented morphological changes similar to the histopathological characteristics of human AMD, in which a defective UPS led to RPE abnormalities such as phagocytosis or degradation of metabolites, the interaction with photoreceptor outer segment, and the transport of nutrients or waste products with choroidal capillaries via Bruch's membrane. Moreover, conditional loss of <i>Ube3d</i> resulted in aberrant molecular characterizations associated with the autophagy–lysosomal pathway, oxidative stress damage, and cell-cycle regulation, which are implicated in AMD pathology. Thus, our findings strengthen and expand the impact of UPS dysfunction on retinal pathophysiology during aging, indicating that genetic <i>Ube3d</i> deficiency in the RPE could lead to the abnormal formation of pigment deposits and secondary fundus alterations. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"261 4","pages":"442-454"},"PeriodicalIF":5.6000,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6201","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/path.6201","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
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Abstract
Several studies have suggested a correlation between the ubiquitin-proteasome system (UPS) and age-related macular degeneration (AMD), with its phenotypic severity ranging from mild visual impairment to blindness, but the mechanism for UPS dysfunction contributing to disease progression is unclear. In this study, we investigated the role of ubiquitin protein ligase E3D (UBE3D) in aging and degeneration in mouse retina. Conditional knockout of Ube3d in the retinal pigment epithelium (RPE) of mice led to progressive and irregular fundus lesions, attenuation of the retinal vascular system, and age-associated deterioration of rod and cone responses. Simultaneously, RPE-specific Ube3d knockout mice also presented morphological changes similar to the histopathological characteristics of human AMD, in which a defective UPS led to RPE abnormalities such as phagocytosis or degradation of metabolites, the interaction with photoreceptor outer segment, and the transport of nutrients or waste products with choroidal capillaries via Bruch's membrane. Moreover, conditional loss of Ube3d resulted in aberrant molecular characterizations associated with the autophagy–lysosomal pathway, oxidative stress damage, and cell-cycle regulation, which are implicated in AMD pathology. Thus, our findings strengthen and expand the impact of UPS dysfunction on retinal pathophysiology during aging, indicating that genetic Ube3d deficiency in the RPE could lead to the abnormal formation of pigment deposits and secondary fundus alterations. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
视网膜色素上皮中Ube3d的条件性丧失加速了小鼠视网膜中与年龄相关的改变
一些研究表明泛素-蛋白酶体系统(UPS)与年龄相关性黄斑变性(AMD)之间存在相关性,其表型严重程度从轻度视力损害到失明不等,但UPS功能障碍导致疾病进展的机制尚不清楚。在这项研究中,我们研究了泛素蛋白连接酶E3D (UBE3D)在小鼠视网膜老化和变性中的作用。条件敲除小鼠视网膜色素上皮(RPE)中的Ube3d导致进行性和不规则眼底病变,视网膜血管系统衰减,以及与年龄相关的视杆和视锥反应恶化。同时,RPE特异性Ube3d敲除小鼠也出现了类似于人类AMD的组织病理学特征的形态学变化,其中UPS缺陷导致RPE异常,如代谢产物的吞噬或降解,与光感受器外段的相互作用,以及营养物质或废物与脉络膜毛细血管通过Bruch膜运输。此外,Ube3d的条件缺失导致与自噬-溶酶体途径、氧化应激损伤和细胞周期调节相关的异常分子特征,这些与AMD病理有关。因此,我们的研究结果加强和扩大了UPS功能障碍对衰老过程中视网膜病理生理的影响,表明RPE中遗传性Ube3d缺乏可能导致色素沉积异常形成和继发性眼底改变。©2023作者。《病理学杂志》由约翰·威利出版;儿子有限公司代表大不列颠及爱尔兰病理学会。
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